Aquilus Pharmaceuticals, Inc. proposes to evaluate the effects of two novel matrix metalloproteinase (MMP) inhibitors in both the medial meniscal tear (MMT) and monoiodoacetate (MIA) rat models of osteoarthritis (OA) with pain read-outs. The goals for Phase I are to scale-up the synthesis of the allosteric, MMP-13 and dual active MMP-2/-9 inhibitors, determine their pharmacokinetics (PK) and run animal efficacy studies in both the MMT and MIA-rat models of OA. The ultimate goal of the proposed work is to evaluate whether a selective MMP inhibitor can be developed for the treatment of OA. PUBLIC HEALTH RELEVANCE: Osteoarthritis (OA) affects an estimated 20 million people and accounts for roughly 25% of office visits to primary care physicians and half of all nonsteroidal anti-inflammatory drug (NSAID) prescriptions for pain. Within the OA pain therapy market there remains a substantial unmet need for drugs that not only reduce joint pain but also treat the disease itself. Currently, there are no diseases modifying drugs in the market to treat Osteoarthritc pain. Aquilus Pharmaceuticals will test a series of highly potent inhibitors of proteins responsible for cartilage degradation in two OA animal pain models. If successful, Aquilus Pharmaceuticals will be able to rapidly bring to the clinic a first in class drug that not only can reduce pain associated with OA but also possibly halt or slow down the disease progression and the eventual need for joint replacement surgery.